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|Systematic (IUPAC) name|
|Licence data||Script error|
|Pregnancy cat.||A (AU) C (US)|
|Legal status||Unscheduled (AU) GSL (UK) OTC (US)|
|Routes||Oral, insufflation, enema|
|PDB ligand ID||CFF (, )|
Caffeine (/,_,_/) is a bitter, white crystalline xanthine alkaloid and a stimulant drug. Caffeine is found in varying quantities in the seeds, leaves, and fruit of some plants, where it acts as a natural pesticide that paralyzes and kills certain insects feeding on the plants, as well as enhancing the reward memory of pollinators. It is most commonly consumed by humans in infusions extracted from the seed of the coffee plant and the leaves of the tea bush, as well as from various foods and drinks containing products derived from the kola nut. Other sources include yerba maté, guarana berries, guayusa, and the yaupon holly.
In humans, caffeine acts as a central nervous system stimulant, temporarily warding off drowsiness and restoring alertness. It is the world's most widely consumed psychoactive drug, but unlike many other psychoactive substances, it is legal and unregulated in nearly all parts of the world. Beverages containing caffeine, such as coffee, tea, soft drinks, and energy drinks, enjoy great popularity. In North America, 90% of adults consume caffeine daily.
Part of the reason caffeine is classified by the Food and Drug Administration as generally recognized as safe is that toxic doses (over 10 grams for an average adult) are much higher than typically used doses (less than 500 milligrams). Ordinary consumption has low health risks, even when carried on for years – there may be a modest protective effect against some diseases, including Parkinson's disease, heart disease, and certain types of cancer. Some people experience sleep disruption if they consume caffeine, especially during the evening hours, but others show little disturbance and the effect of caffeine on sleep is highly variable.
Evidence of a risk to pregnancy is equivocal, with some authorities concluding that it is wise for pregnant women to limit consumption to the equivalent of two cups of coffee per day or less. Caffeine has pressor and mild diuretic effects when administered to people who are not used to it, but regular users develop a tolerance to this effect, and studies have generally failed to support the common notion that ordinary consumption contributes significantly to dehydration. With heavy use, tolerance develops rapidly to autonomic effects such as elevated heart rate and muscle twitching, but not to the cognitive or arousal effects of caffeine. The degree to which caffeine can produce significant dependency and caffeine addiction remains a subject of controversy in the medical literature.
- 1 Health effects
- 2 Sources and consumption
- 3 Chemical properties and biosynthesis
- 4 Pharmacology
- 5 Detection in biological fluids
- 6 Decaffeination
- 7 History
- 8 Religion
- 9 Other organisms
- 10 References
- 11 Bibliography
- 12 External links
Caffeine is a central nervous system and metabolic stimulant, and is used both recreationally and medically to reduce physical fatigue and to restore alertness when drowsiness occurs. It produces increased wakefulness, faster and clearer flow of thought, increased focus, and better general body coordination. The amount of caffeine needed to produce effects varies from person to person, depending on body size and degree of tolerance. Effects begin less than an hour after consumption, and a moderate dose usually wears off in about five hours.
Caffeine has a number of effects on sleep, but does not affect all people in the same way. It improves performance during sleep deprivation but may lead to subsequent insomnia. In shift workers it leads to fewer mistakes caused by tiredness. In athletics, moderate doses of caffeine can improve sprint, endurance, and team sports performance, but the improvements are usually not very large. Some evidence suggests that coffee does not produce the ergogenic effects observed in other caffeine sources. High doses of caffeine, however, can impair athletic performance by interfering with coordination. There is also evidence that caffeine may be helpful at high altitude.
Consumption of 1000–1500 mg per day is associated with a condition known as caffeinism. Caffeinism usually combines caffeine dependency with a wide range of unpleasant physical and mental conditions including nervousness, irritability, restlessness, insomnia, headaches, and heart palpitations after caffeine use.
Coffee consumption is associated with a lower overall risk of cancer. This is primarily due to a decrease in the risks of hepatocellular and endometrial cancer, but it may also have a modest effect on colorectal cancer. There does not appear to be a significant protective effect against other types of cancers, and heavy coffee consumption may increase the risk of bladder cancer. Moderate coffee consumption may decrease the risk of cardiovascular disease, and it may somewhat reduce the risk of type 2 diabetes. Drinking four or more cups of coffee per day does not affect the risk of hypertension compared to drinking little or no coffee. However those who drink 1–3 cups per day may be at a slightly increased risk. Caffeine increases intraocular pressure in those with glaucoma but does not appear to affect normal individuals. It may protect people from liver cirrhosis. There is no evidence that coffee stunts a child's growth. Caffeine may increase the effectiveness of some medications including ones used to treat headaches. Similarly, intravenous caffeine is often used in hospitals to provide temporary pain relief for headaches caused by low cerebrospinal fluid pressure.
Caffeine consumption during pregnancy does not appear to increase the risk of congenital malformations, miscarriage or growth retardation even when consumed in moderate to high amounts. However as the data supporting this conclusion is of poor quality some suggest limiting caffeine consumption during pregnancy. For example the UK Food Standards Agency has recommended that pregnant women should limit their caffeine intake, out of prudence, to less than 200 mg of caffeine a day – the equivalent of two cups of instant coffee, or one and a half to two cups of fresh coffee. The American Congress of Obstetricians and Gynecologists (ACOG) concluded in 2010 that caffeine consumption is safe up to 200 mg per day in pregnant women. Although the evidence that caffeine may be harmful during pregnancy is equivocal, there is some evidence that the hormonal changes associated with pregnancy slow the metabolic clearance of caffeine from the system, causing a given dose to have longer-lasting effects (as long as 15 hours in the third trimester).
Caffeine is a weak bronchodilator. In clinical tests on adults with asthma, at fairly low doses (5mg/kg of body weight), caffeine has been shown to provide a small improvement in lung function, such that it needs to be controlled for in diagnostic tests. Caffeine is the primary treatment of the breathing disorders apnea of prematurity and may also be effective in preventing bronchopulmonary dysplasia in premature infants. The only short-term risk associated with caffeine citrate treatment is a temporary reduction in weight gain during the therapy, and longer term studies (18 to 21 months) have shown lasting benefits of treatment of premature infants with caffeine. While some authors have raised the possibility of subtle long-term problems, follow-up neurological data at 18 months and at five years after neonatal caffeine treatment revealed the opposite; treatment appears to be neuroprotective, as caffeine-treated children were significantly less likely to have cerebral palsy and had reduced rates of language and cognitive delay.
When doses of caffeine equivalent to 2–3 cups of coffee are administered to people who have not consumed caffeine during prior days, they produce a mild increase in urinary output. Because of this diuretic effect, some authorities have recommended that athletes or airline passengers avoid caffeine to reduce the risk of dehydration. Most people who consume caffeine, however, ingest it daily. Regular users of caffeine have been shown to develop a strong tolerance to the diuretic effect, and studies have generally failed to support the notion that ordinary consumption of caffeinated beverages contributes significantly to dehydration, even in athletes.
The US National Institutes of Health states: "[Too] much caffeine can make you restless, anxious, and irritable. It may also keep you from sleeping well and cause headaches, abnormal heart rhythms, or other problems. If you stop using caffeine, you could get withdrawal symptoms. Some people are more sensitive to the effects of caffeine than others. They should limit their use of caffeine. So should pregnant and nursing women."
Four caffeine-induced disorders are recognized by the American Psychiatric Association (APA) including: caffeine intoxication, caffeine-induced sleep disorder, caffeine-induced anxiety disorder and caffeine-related disorder not otherwise specified (NOS). The DSM-IV defines a person with caffeine-induced sleep disorder as an individual who regularly ingests high doses of caffeine sufficient to induce a significant disturbance in his or her sleep, sufficiently severe to warrant clinical attention. As of 2010 the effect of caffeine on people with ADHD is not known. Some studies have however found modest protective effect against Alzheimer disease, but the evidence is inconclusive.
Caffeine can have negative effects on anxiety disorders. A number of clinical studies have shown a positive association between caffeine and anxiogenic effects and/or panic disorder. At high doses, typically greater than 300 mg, caffeine can both cause and worsen anxiety or, rarely, trigger mania or psychosis. In moderate doses caffeine may reduce symptoms of depression and lower suicide risk. In moderate doses caffeine typically does not affect learning or memory, and can improve cognitive functions, especially in people who are fatigued, possibly due to its effect on alertness. For some people, anxiety can be very much reduced by discontinuing caffeine use.
Caffeine overdose can result in a state of central nervous system over-stimulation called caffeine intoxication (DSM-IV 305.90). This syndrome typically occurs only after ingestion of large amounts of caffeine, well over the amounts found in typical caffeinated beverages and caffeine tablets (e.g., more than 400–500 mg at a time). The symptoms of caffeine intoxication are comparable to the symptoms of overdoses of other stimulants: they may include restlessness, fidgeting, anxiety, excitement, insomnia, flushing of the face, increased urination, gastrointestinal disturbance, muscle twitching, a rambling flow of thought and speech, irritability, irregular or rapid heart beat, and psychomotor agitation. In cases of much larger overdoses, mania, depression, lapses in judgment, disorientation, disinhibition, delusions, hallucinations, or psychosis may occur, and rhabdomyolysis (breakdown of skeletal muscle tissue) can be provoked.
Extreme overdose can result in death. The median lethal dose (LD50) given orally is 192 milligrams per kilogram in rats. The LD50 of caffeine in humans is dependent on individual sensitivity, but is estimated to be about 150 to 200 milligrams per kilogram of body mass or roughly 80 to 100 cups of coffee for an average adult. Though achieving lethal dose of caffeine would be difficult with regular coffee, it is easier to reach high doses with caffeine pills, and the lethal dose can be lower in individuals whose ability to metabolize caffeine is impaired. Chronic liver disease is one factor that can slow the metabolism of caffeine. There has been a reported death of a man who had liver cirrhosis overdosing on caffeinated mints. Drugs such as fluvoxamine or levofloxacin can have a similar effect by blocking the liver enzyme responsible for the metabolism of caffeine, thus increasing the central effects and blood concentrations of caffeine five-fold. The exact cause of death in such cases is uncertain, but may result from cardiac arrhythmia leading to cardiac arrest.
Treatment of severe caffeine intoxication is generally supportive, providing treatment of the immediate symptoms, but if the patient has very high serum levels of caffeine then peritoneal dialysis, hemodialysis, or hemofiltration may be required.
Addiction and tolerance
With repetitive use, physical dependence or addiction may occur. Also, some effects of caffeine, particularly the autonomic effects, decrease over time, a phenomenon known as a tolerance. Tolerance develops quickly to some (but not all) effects of caffeine, especially among heavy coffee and energy drink consumers. Some coffee drinkers develop tolerance to its sleep-disrupting effects, but others apparently do not.
Withdrawal symptoms – including headaches, irritability, inability to concentrate, drowsiness, insomnia, and pain in the stomach, upper body, and joints – may appear within 12 to 24 hours after discontinuation of caffeine intake, peak at roughly 48 hours, and usually last from 2 to 9 days. Withdrawal headaches are experienced by 52% of people who stopped consuming caffeine for two days after an average of 235 mg caffeine per day prior to that. In prolonged caffeine users, symptoms such as increased depression and anxiety, nausea, vomiting, physical pains and intense desire for caffeine are also reported. Peer knowledge, support and interaction may aid withdrawal.
Caffeine withdrawal is categorized as a mental disorder in the DSM-5 (the 5th edition of the Diagnostic and Statistical Manual published by the American Psychiatric Association). Previous versions of the manual included "caffeine intoxication" but not caffeine withdrawal.
Sources and consumption
|Product||Serving size||Caffeine per serving (mg)||Caffeine (mg/L)|
|Caffeine tablet (regular-strength)||1 tablet||100||—|
|Caffeine tablet (extra-strength)||1 tablet||200||—|
|Excedrin tablet||1 tablet||65||—|
|Hershey's Special Dark (45% cacao content)||1 bar (43 g or 1.5 oz)||31||—|
|Hershey's Milk Chocolate (11% cacao content)||1 bar (43 g or 1.5 oz)||10||—|
|Percolated coffee||207 mL (7.0 US fl oz)||80–135||386–652|
|Drip coffee||207 mL (7.0 US fl oz)||115–175||555–845|
|Coffee, decaffeinated||207 mL (7.0 US fl oz)||5–15||24–72|
|Coffee, espresso||44Expression error: Unexpected < operator.60 mL (1.5Expression error: Unexpected < operator.2.0 US fl oz)||100||1,691–2,254|
|Tea – black, green, and other types, – steeped for 3 min.||177 millilitres (6.0 US fl oz)||22–74||124–416|
|Guayakí yerba mate (loose leaf)||6 g (0.21 oz)||85||approx. 358|
|Coca-Cola Classic||355 mL (12.0 US fl oz)||34||96|
|Mountain Dew||355 mL (12.0 US fl oz)||54||154|
|Pepsi Max||355 mL (12.0 US fl oz)||69||194|
|Guaraná Antarctica||350 mL (12 US fl oz)||30||100|
|Jolt Cola||695 mL (23.5 US fl oz)||280||403|
|Red Bull||250 mL (8.5 US fl oz)||80||320|
Global consumption of caffeine has been estimated at 120,000 tonnes per year, making it the world's most popular psychoactive substance. This amounts to one serving of a caffeinated beverage for every person every day.
Caffeine is found in many plant species, where it acts as a natural pesticide, with high caffeine levels being observed in seedlings still developing foliage but lacking mechanical protection; caffeine paralyzes and kills certain insects feeding on the plant. High caffeine levels have also been found in the surrounding soil of coffee bean seedlings. Therefore, caffeine is understood to have a natural function as both a natural pesticide and an inhibitor of seed germination of other nearby coffee seedlings, thus giving it a better chance of survival. Caffeine has also been found to enhance the reward memory of honeybees, improving the reproductive success of the plant.
Common sources of caffeine are coffee, tea, soft drinks and energy drinks, caffeine supplements, and (to a lesser extent) chocolate derived from cocoa beans. Less commonly used sources of caffeine include the yerba maté, guarana and ilex guayusa plants, which are sometimes used in the preparation of teas and energy drinks. Two of caffeine's alternative names, mateine and guaranine, are derived from the names of these plants.
The disparity in experience and effects between the various natural caffeine sources could be because plant sources of caffeine also contain widely varying mixtures of other xanthine alkaloids, including the cardiac stimulants theophylline and theobromine, and other substances such as polyphenols that can form insoluble complexes with caffeine.Template:Clarify
One of the world's primary sources of caffeine is the coffee "bean" (which is the seed of the coffee plant), from which coffee is brewed. Caffeine content in coffee varies widely depending on the type of coffee bean and the method of preparation used; even beans within a given bush can show variations in concentration. In general, one serving of coffee ranges from 80 to 100 milligrams, for a single shot (30 milliliters) of arabica-variety espresso, to approximately 100–125 milligrams for a cup (120 milliliters) of drip coffee. Arabica coffee typically contains half the caffeine of the robusta variety.
Tea contains more caffeine than coffee by dry weight. A typical serving, however, contains much less, since tea is normally brewed much weaker. Also contributing to caffeine content are growing conditions, processing techniques, and other variables. Thus, certain types of tea may contain somewhat more caffeine than other teas.
Tea contains small amounts of theobromine and slightly higher levels of theophylline than coffee. Preparation and many other factors have a significant impact on tea, and color is a very poor indicator of caffeine content. Teas like the pale Japanese green tea, gyokuro, for example, contain far more caffeine than much darker teas like lapsang souchong, which has very little.
Caffeine is also a common ingredient of soft drinks, such as cola, originally prepared from kola nuts. Soft drinks typically contain about 10 to 50 milligrams of caffeine per serving. By contrast, energy drinks, such as Red Bull, can start at 80 milligrams of caffeine per serving. The caffeine in these drinks either originates from the ingredients used or is an additive derived from the product of decaffeination or from chemical synthesis. Guarana, a prime ingredient of energy drinks, contains large amounts of caffeine with small amounts of theobromine and theophylline in a naturally occurring slow-release excipient.
Chocolate derived from cocoa beans contains a small amount of caffeine. The weak stimulant effect of chocolate may be due to a combination of theobromine and theophylline, as well as caffeine. A typical 28-gram serving of a milk chocolate bar has about as much caffeine as a cup of decaffeinated coffee, although dark chocolate has about the same caffeine as coffee by weight. Some dark chocolate currently in production contains as much as 160 mg per 100 g – which is double the caffeine content of the highest caffeinated drip coffee by weight.
Various manufacturers market caffeine tablets, claiming that using caffeine of pharmaceutical quality improves mental alertness. These effects have been borne out by research that shows caffeine use (whether in tablet form or not) results in decreased fatigue and increased attentiveness.
These tablets are commonly used by students studying for their exams and by people who work or drive for long hours. One U.S. company is also marketing dissolving caffeine strips as an alternative to energy drinks. Another unusual intake route is SpazzStick, a caffeinated lip balm. As of 2013, a number of innovative caffeinated products such as Alert Energy Caffeine Gum, a Wrigley product, had been introduced in the United States, but were under scrutiny; after announcement of an investigation by the FDA of the health effects of added caffeine in foods, Alert Energy Caffeine Gum was voluntarily withdrawn from sale.
Chemical properties and biosynthesis
Pure anhydrous caffeine is a white colorless powder with a melting point of 227–228 °C. Caffeine is moderately soluble in water at room temperature (2 g/100 mL), but very soluble in boiling water (66 g/100 mL). It is also moderately soluble in ethanol (1.5 g/100 mL). It is weakly basic (pKa = ~0.6) requiring strong acid to protonate it.
The xanthine core of caffeine contains two fused rings, a pyrimidinedione and imidazole. The pyrimidinedione in turn contains two amide functional groups that exist predominately in a zwitterionic resonance form where the nitrogen atoms are double bonded to their adjacent amide carbons atoms. Hence all six of the atoms within the pyrimidinedione ring system are sp2 hybridized and planar. Therefore the fused 5,6 ring core of caffeine contains a total of ten pi electrons and hence according to Hückel's rule is aromatic.
Caffeine is synthesized in plants from the purine nucleotides AMP, GMP, and IMP. These in turn are transformed into xanthosine and then theobromine, the latter being the penultimate precursor of caffeine. Being readily available as a byproduct of decaffeination, caffeine is not usually synthesized chemically. If desired, it may be synthesized from dimethylurea and malonic acid.
Inside the body caffeine acts through several mechanisms, but its most important effect is to counteract a substance called adenosine that naturally circulates at high levels throughout the body, and especially in the nervous system. In the brain, adenosine plays a generally protective role, part of which is to reduce neural activity levels – for example, there is some evidence that adenosine helps to induce torpor in animals that seasonally hibernate.
Mechanism of actionAdenosine acts as an inhibitory neurotransmitter that suppresses activity in the central nervous system. "Largely as a consequence of its blockade of adenosine receptors, caffeine also has profound effects on most of the other major neurotransmitters, including dopamine, acetylcholine, serotonin, and, in high doses, on norepinephrine", and to a small extent epinephrine, glutamate, and cortisol. At high doses, exceeding 500 milligrams, caffeine inhibits GABA neurotransmission. GABA reduction explains why caffeine increases anxiety, insomnia, rapid heart and respiration rate.
Because caffeine is both water- and lipid-soluble, it readily crosses the blood–brain barrier that separates the bloodstream from the interior of the brain. Once in the brain, the principal mode of action is as a nonselective antagonist of adenosine receptors (in other words, an agent that reduces the effects of adenosine). The caffeine molecule is structurally similar to adenosine, and is capable of binding to adenosine receptors on the surface of cells without activating them, thereby acting as a competitive inhibitor.
Adenosine is found in every part of the body, because it plays a role in the fundamental adenosine triphosphate (ATP) related energy producing mechanism and is also needed for RNA synthesis, but it has additional functions in the brain. The evidence indicates that brain adenosine acts to protect the brain by suppressing neural activity and by increasing blood flow via receptors located on vascular smooth muscle. Brain adenosine levels are increased by various types of metabolic stress, including lack of oxygen and interruption of blood flow. There is evidence that adenosine functions as a synaptically released neurotransmitter in some parts of the brain; however, stress-related adenosine increases appear to be produced mainly by extracellular metabolism of ATP. Unlike most neurotransmitters, adenosine does not seem to be packaged into vesicles that are released in a voltage-controlled manner, but the possibility of such a mechanism has not been fully ruled out.
Several classes of adenosine receptors have been described, with different anatomical distributions. A1 receptors are widely distributed, and act to inhibit calcium uptake. A2A receptors are heavily concentrated in the basal ganglia, an area that plays a critical role in behavior control, but can be found in other parts of the brain as well, in lower densities. There is evidence that A2A receptors interact with the dopamine system, which is involved in reward and arousal. (A2A receptors can also be found on arterial walls and blood cell membranes.)
Beyond its general neuroprotective effects, there are reasons to believe that adenosine may be more specifically involved in control of the sleep–wake cycle. Robert McCarley and his colleagues have argued that accumulation of adenosine may be a primary cause of the sensation of sleepiness that follows prolonged mental activity, and that the effects may be mediated both by inhibition of wake-promoting neurons via A1 receptors, and activation of sleep-promoting neurons via indirect effects on A2A receptors. More recent studies have provided additional evidence for the importance of A2A, but not A1, receptors.
Caffeine, like other xanthines, also acts as a phosphodiesterase inhibitor. As a competitive nonselective phosphodiesterase inhibitor, caffeine raises intracellular cAMP, activates protein kinase A, inhibits TNF-alpha and leukotriene synthesis, and reduces inflammation and innate immunity.
A number of potential mechanisms have been proposed for the athletic performance-enhancing effects of caffeine. In the classic, or metabolic theory, caffeine may increase fat utilization and decrease glycogen utilization. Caffeine mobilizes free fatty acids from fat and/or intramuscular triglycerides by increasing circulating epinephrine levels. The increased availability of free fatty acids increases fat oxidation and spares muscle glycogen, thereby enhancing endurance performance. In the nervous system, caffeine may reduce the perception of effort by lowering the neuron activation threshold, making it easier to recruit the muscles for exercise.
Metabolites of caffeine also contribute to caffeine's effects. Paraxanthine is responsible for an increase in the lipolysis process, which releases glycerol and fatty acids into the blood to be used as a source of fuel by the muscles. Theobromine is a vasodilator that increases the amount of oxygen and nutrient flow to the brain and muscles. Theophylline acts as a smooth muscle relaxant that chiefly affects bronchioles and acts as a chronotrope and inotrope that increases heart rate and force of contraction.
Caffeine from coffee or other beverages is absorbed by the small intestine within 45 minutes of ingestion and then distributed throughout all tissues of the body. Peak blood concentration is reached within 1–2 hours. It is eliminated by first-order kinetics. Caffeine can also be absorbed rectally, evidenced by the formulation of suppositories of ergotamine tartrate and caffeine (for the relief of migraine) and chlorobutanol and caffeine (for the treatment of hyperemesis).
The biological half-life of caffeine – the time required for the body to eliminate one-half of the total amount of caffeine – varies widely among individuals according to such factors as age, liver function, pregnancy, some concurrent medications, and the level of enzymes in the liver needed for caffeine metabolism. It can also be significantly altered by drugs or hormonal states. In healthy adults, caffeine's half-life has been measured with a range of results. Some measures get 4.9 hours, and others are at around 6 hours. Heavy cigarette smokers show a decrease in half-life of 30–50%, oral contraceptives can double it, and pregnancy can raise it even more, to as much as 15 hours during the last trimester. In newborn infants the half-life can be 80 hours or more; however it drops very rapidly with age, possibly to less than the adult value by the age of 6 months. The antidepressant fluvoxamine (Luvox) reduces the clearance of caffeine by more than 90%, and prolongs its elimination half-life more than tenfold; from 4.9 hours to 56 hours.
Caffeine is metabolized in the liver by the cytochrome P450 oxidase enzyme system, in particular, by the CYP1A2 isozyme, into three dimethylxanthines, each of which has its own effects on the body:
- Paraxanthine (84%): Increases lipolysis, leading to elevated glycerol and free fatty acid levels in the blood plasma.
- Theobromine (12%): Dilates blood vessels and increases urine volume. Theobromine is also the principal alkaloid in the cocoa bean, and therefore chocolate.
- Theophylline (4%): Relaxes smooth muscles of the bronchi, and is used to treat asthma. The therapeutic dose of theophylline, however, is many times greater than the levels attained from caffeine metabolism.
A 2011 review found that habitual caffeine intake was associated with a variation in two genes that regulate how quickly the body processes caffeine. Subjects who had a high-intake mutation on both chromosomes consumed 40 mg more caffeine per day than people who did not.
Detection in biological fluids
Caffeine can be quantified in blood, plasma, or serum to monitor therapy in neonates, confirm a diagnosis of poisoning, or facilitate a medicolegal death investigation. Plasma caffeine levels are usually in the range of 2–10 mg/L in coffee drinkers, 12–36 mg/L in neonates receiving treatment for apnea, and 40–400 mg/L in victims of acute overdosage. Urinary caffeine concentration is frequently measured in competitive sports programs, for which a level in excess of 15 mg/L is usually considered to represent abuse.
Extraction of caffeine from coffee, to produce decaffeinated coffee and caffeine, is an importantTemplate:Quantify industrial process and can be performed using a number of solvents. Benzene, chloroform, trichloroethylene, and dichloromethane have all been used over the years but for reasons of safety, environmental impact, cost, and flavor, they have been superseded by the following main methods:
- Water extraction: Coffee beans are soaked in water. The water, which contains many other compounds in addition to caffeine and contributes to the flavor of coffee, is then passed through activated charcoal, which removes the caffeine. The water can then be put back with the beans and evaporated dry, leaving decaffeinated coffee with its original flavor. Coffee manufacturers recover the caffeine and resell it for use in soft drinks and over-the-counter caffeine tablets.
- Supercritical carbon dioxide extraction: Supercritical carbon dioxide is an excellent nonpolar solvent for caffeine, and is safer than the organic solvents that are otherwise used. The extraction process is simple: Template:CO2 is forced through the green coffee beans at temperatures above 31.1 °C and pressures above 73 atm. Under these conditions, Template:CO2 is in a "supercritical" state: It has gaslike properties that allow it to penetrate deep into the beans but also liquid-like properties that dissolve 97–99% of the caffeine. The caffeine-laden Template:CO2 is then sprayed with high pressure water to remove the caffeine. The caffeine can then be isolated by charcoal adsorption (as above) or by distillation, recrystallization, or reverse osmosis.
- Extraction by organic solvents: Certain organic solvents such as ethyl acetate present much less health and environmental hazard than chlorinated and aromatic organic solvents used formerly. Another method is to use triglyceride oils obtained from spent coffee grounds.
"Decaffeinated" coffees do in fact contain caffeine in many cases — some commercially available decaffeinated coffee products contain considerable levels. One study found that decaffeinated coffee contained 10 mg of caffeine per cup, compared to approximately 85 mg of caffeine per cup for regular coffee.
According to Chinese legend, the Chinese emperor Shennong, reputed to have reigned in about 3000 BCE, accidentally discovered tea when he noted that when certain leaves fell into boiling water, a fragrant and restorative drink resulted. Shennong is also mentioned in Lu Yu's Cha Jing, a famous early work on the subject of tea.
The earliest credible evidence of either coffee drinking or knowledge of the coffee tree appears in the middle of the fifteenth century, in the Sufi monasteries of the Yemenin southern Arabia. From Mocha, coffee spread to Egypt and North Africa, and by the 16th century, it had reached the rest of the Middle East, Persia and Turkey. From the Middle East, coffee drinking spread to Italy, then to the rest of Europe, and coffee plants were transported by the Dutch to the East Indies and to the Americas.
Use of the kola nut, like the coffee berry and tea leaf, appears to have ancient origins. It is chewed in many West African cultures, individually or in a social setting, to restore vitality and ease hunger pangs. In 1911, kola became the focus of one of the earliest documented health scares, when the US government seized 40 barrels and 20 kegs of Coca-Cola syrup in Chattanooga, Tennessee, alleging the caffeine in its drink was "injurious to health". Although the judge ruled in favor of Coca-Cola, two bills were introduced to the U.S. House of Representatives in 1912 to amend the Pure Food and Drug Act, adding caffeine to the list of "habit-forming" and "deleterious" substances, which must be listed on a product's label.[unreliable source?]
The earliest evidence of cocoa bean use comes from residue found in an ancient Mayan pot dated to 600 BCE. In the New World, chocolate was consumed in a bitter and spicy drink called xocolatl, often seasoned with vanilla, chile pepper, and achiote. Xocolatl was believed to fight fatigue, a belief probably attributable to the theobromine and caffeine content. Chocolate was an important luxury good throughout pre-Columbian Mesoamerica, and cocoa beans were often used as currency.
Xocolatl was introduced to Europe by the Spaniards, and became a popular beverage by 1700. The Spaniards also introduced the cacao tree into the West Indies and the Philippines. It was used in alchemical processes, where it was known as "black bean".
The leaves and stems of the yaupon holly (Ilex vomitoria) were used by Native Americans to brew a tea called asi or the "black drink". Archaeologists have found evidence of this use stretch back far into antiquity, possibly dating to Late Archaic times.
In 1819, the German chemist Friedlieb Ferdinand Runge isolated relatively pure caffeine for the first time; he called it "Kaffebase" (i.e. a base that exists in coffee). According to Runge, he did this at the behest of Johann Wolfgang von Goethe. In 1821, caffeine was isolated both by the French chemist Pierre Jean Robiquet and by another pair of French chemists, Pierre-Joseph Pelletier and Joseph Bienaimé Caventou, according to Swedish chemist Jöns Jacob Berzelius in his yearly journal. Furthermore, Berzelius stated that the French chemists had made their discoveries independently of any knowledge of Runge's or each other's work. However, Berzelius later acknowledged Runge's priority in the extraction of caffeine, stating: "However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris."
Pelletier's article on caffeine was the first to use the term in print (in the French form Caféine from the French word for coffee: café). It corroborates Berzelius's account:
Caffeine, noun (feminine). Crystallizable substance discovered in coffee in 1821 by Mr. Robiquet. During the same period – while they were searching for quinine in coffee because coffee is considered by several doctors to be a medicine that reduces fevers and because coffee belongs to the same family as the cinchona [quinine] tree – on their part, Messrs. Pelletier and Caventou obtained caffeine; but because their research had a different goal and because their research had not been finished, they left priority on this subject to Mr. Robiquet. We do not know why Mr. Robiquet has not published the analysis of coffee which he read to the Pharmacy Society. Its publication would have allowed us to make caffeine better known and give us accurate ideas of coffee's composition ...
In 1895, German chemist Hermann Emil Fischer (1852–1919) first synthesized caffeine from raw materials (i.e. a "total synthesis"), and two years later, he also derived the structural formula of the compound. This was part of the work for which Fischer was awarded the Nobel Prize in 1902.
Historically, coffee and thus caffeine was illegal for some classes in Mecca in parts of the 16th century, and in the Ottoman empire. Charles II of England tried to ban it in 1676, Frederick II of Prussia banned it in 1777, and coffee was banned in Sweden in the years 1756–1769, 1794–1796, 1799–1802, and 1817–1823. The bans on coffee have often had religious, economic, or political reasons rather than being based on concerns for the well-being of the population.
Some Seventh-day Adventists, Church of God (Restoration) adherents, and Christian Scientists do not consume caffeine. Some from these religions believe that one is not supposed to consume a non-medical, psychoactive substance, or believe that one is not supposed to consume a substance that is addictive. The Church of Jesus Christ of Latter-day Saints has said the following with regard to caffeinated beverages: "With reference to cola drinks, the Church has never officially taken a position on this matter, but the leaders of the Church have advised, and we do now specifically advise, against the use of any drink containing harmful habit-forming drugs under circumstances that would result in acquiring the habit. Any beverage that contains ingredients harmful to the body should be avoided."
Gaudiya Vaishnavas generally also abstain from caffeine, as it is alleged to cloud the mind and over-stimulate the senses. To be initiated under a guru, one must have had no caffeine, alcohol, nicotine or other drugs, for at least a year.
Caffeinated beverages are widely consumed by Muslims today; in the 16th century, some Muslim authorities made unsuccessful attempts to ban them as forbidden "intoxicating beverages" under Islamic dietary laws.
While safe in humans, caffeine is considerably more toxic to various animals, such as dogs and birds. The increased toxicity of caffeine in some animals is at least partly due to a poorer ability to metabolize the compound. Caffeine also has a pronounced effect on mollusks, various insects, and spiders.
- Lovett R (24 September 2005). "Coffee: The demon drink?". New Scientist (2518). http://www.newscientist.com/article.ns?id=mg18725181.700.
- Cano-Marquina A, Tarín JJ, Cano A (May 2013). "The impact of coffee on health". Maturitas 75 (1): 7–21. doi:10.1016/j.maturitas.2013.02.002. PMID 23465359. http://linkinghub.elsevier.com/retrieve/pii/S0378-5122(13)00047-9. Retrieved 15 January 2014.
- Qi H, Li S (23 July 2003). "Dose-response meta-analysis on coffee, tea and caffeine consumption with risk of Parkinson's disease". Geriatr Gerontol Int. doi:10.1111/ggi.12123. PMID 23879665.
- Ding, M; Bhupathiraju, SN; Satija, A; van Dam, RM; Hu, FB (11 February 2014). "Long-term coffee consumption and risk of cardiovascular disease: a systematic review and a dose-response meta-analysis of prospective cohort studies.". Circulation 129 (6): 643–59. doi:10.1161/circulationaha.113.005925. PMID 24201300.
- Mayo Clinic staff. "Pregnancy Nutrition: Foods to avoid during pregnancy". Mayo Clinic. http://www.mayoclinic.com/health/pregnancy-nutrition/PR00109/NSECTIONGROUP=2. Retrieved 15 April 2012.
- American College of Obstetricians and Gynecologists (August 2010). "ACOG CommitteeOpinion No. 462: Moderate caffeine consumption during pregnancy". Obstet Gynecol 116 (2 Pt 1): 467–8. doi:10.1097/AOG.0b013e3181eeb2a1. PMID 20664420.
- Nehlig A, Daval JL, Debry G (1992). "Caffeine and the central nervous system: mechanisms of action, biochemical, metabolic and psychostimulant effects". Brain Res. Brain Res. Rev. 17 (2): 139–70. doi:10.1016/0165-0173(92)90012-B. PMID 1356551.
- Bolton S (1981). "Caffeine: Psychological Effects, Use and Abuse". Orthomolecular Psychiatry 10 (3): 202–211. http://intraspec.ca/1981-v10n03-p202.pdf.
- Snel J, Lorist MM (2011). "Effects of caffeine on sleep and cognition". Prog. Brain Res.. Progress in Brain Research 190: 105–17. doi:10.1016/B978-0-444-53817-8.00006-2. ISBN 978-0-444-53817-8. PMID 21531247.
- Ker K, Edwards PJ, Felix LM, Blackhall K, Roberts I (2010). Ker, Katharine. ed. "Caffeine for the prevention of injuries and errors in shift workers". Cochrane Database Syst Rev (5): CD008508. doi:10.1002/14651858.CD008508. PMID 20464765.
- Bishop D (2010). "Dietary supplements and team-sport performance". Sports Med 40 (12): 995–1017. doi:10.2165/11536870-000000000-00000. PMID 21058748.
- Conger SA, Warren GL, Hardy MA, Millard-Stafford ML (2011). "Does caffeine added to carbohydrate provide additional ergogenic benefit for endurance?". Int J Sport Nutr Exerc Metab 21 (1): 71–84. PMID 21411838.
- Astorino TA, Roberson DW (2010). "Efficacy of acute caffeine ingestion for short-term high-intensity exercise performance: a systematic review". J Strength Cond Res 24 (1): 257–65. doi:10.1519/JSC.0b013e3181c1f88a. PMID 19924012.
- Graham TE, Hibbert E, Sathasivam P (September 1998). "Metabolic and exercise endurance effects of coffee and caffeine ingestion". J. Appl. Physiol. 85 (3): 883–9. PMID 9729561. http://jap.physiology.org/content/85/3/883.full.
- Tarnopolsky MA (2010). "Caffeine and creatine use in sport". Ann. Nutr. Metab. 57 Suppl 2: 1–8. doi:10.1159/000322696. PMID 21346331.
- Hackett PH (2010). "Caffeine at high altitude: java at base cAMP". High Alt. Med. Biol. 11 (1): 13–7. doi:10.1089/ham.2009.1077. PMID 20367483.
- Winston AP, Hardwick E, Jaberi N (2005). "Neuropsychiatric effects of caffeine". Advances in Psychiatric Treatment 11: 432–439. doi:10.1192/apt.11.6.432. http://apt.rcpsych.org/content/11/6/432.full. Retrieved 19 December 2013.
- Iancu I, Olmer A, Strous RD (2007). "Caffeinism: History, clinical features, diagnosis, and treatment". in Smith BD, Gupta U, Gupta BS. Caffeine and activation theory: effects on health and behavior. CRC Press. pp. 331–344. ISBN 978-0-8493-7102-8. http://books.google.com/books?id=sm2ZySXTm7oC&pg=PA331. Retrieved 15 January 2014.
- Nkondjock A (May 2009). "Coffee consumption and the risk of cancer: an overview". Cancer Lett. 277 (2): 121–5. doi:10.1016/j.canlet.2008.08.022. PMID 18834663.
- Arab L (2010). "Epidemiologic evidence on coffee and cancer". Nutrition and cancer 62 (3): 271–83. doi:10.1080/01635580903407122. PMID 20358464.
- van Dam RM (2008). "Coffee consumption and risk of type 2 diabetes, cardiovascular diseases, and cancer". Applied physiology, nutrition, and metabolism 33 (6): 1269–1283. doi:10.1139/H08-120. PMID 19088789.
- Zhang Z, Hu G, Caballero B, Appel L, Chen L (June 2011). "Habitual coffee consumption and risk of hypertension: a systematic review and meta-analysis of prospective observational studies". Am. J. Clin. Nutr. 93 (6): 1212–9. doi:10.3945/ajcn.110.004044. PMID 21450934.
- Li M, Wang M, Guo W, Wang J, Sun X (March 2011). "The effect of caffeine on intraocular pressure: a systematic review and meta-analysis". Graefes Arch. Clin. Exp. Ophthalmol. 249 (3): 435–42. doi:10.1007/s00417-010-1455-1. PMID 20706731.
- Muriel P, Arauz J (2010). "Coffee and liver diseases". Fitoterapia 81 (5): 297–305. doi:10.1016/j.fitote.2009.10.003. PMID 19825397.
- O'Connor A (2007). Never shower in a thunderstorm : surprising facts and misleading myths about our health and the world we live in (1st ed.). New York: Times Books. p. 144. ISBN 978-0-8050-8312-5. http://books.google.com/books?id=neuEbVUZik0C&pg=PA144. Retrieved 15 January 2014.
- Gilmore B, Michael M (February 2011). "Treatment of acute migraine headache". Am Fam Physician 83 (3): 271–80. PMID 21302868.
- Brent RL, Christian MS, Diener RM (2011). "Evaluation of the reproductive and developmental risks of caffeine". Birth Defects Res. B Dev. Reprod. Toxicol. 92 (2): 152–87. doi:10.1002/bdrb.20288. PMID 21370398.
- Kuczkowski KM (2009). "Caffeine in pregnancy". Arch. Gynecol. Obstet. 280 (5): 695–8. doi:10.1007/s00404-009-0991-6. PMID 19238414.
- Jahanfar S, Sharifah H (2009). Jahanfar, Shayesteh. ed. "Effects of restricted caffeine intake by mother on fetal, neonatal and pregnancy outcome". Cochrane Database Syst Rev (2): CD006965. doi:10.1002/14651858.CD006965.pub2. PMID 19370665.
- "Food Standards Agency publishes new caffeine advice for pregnant women". http://www.food.gov.uk/news/pressreleases/2008/nov/caffeineadvice. Retrieved 3 August 2009.
- Fredholm BB, Bättig K, Holmén J, Nehlig A, Zvartau EE (1999). "Actions of caffeine in the brain with special reference to factors that contribute to its widespread use". Pharmacol. Rev. 51 (1): 83–133. PMID 10049999.
- Welsh, EJ.; Bara, A.; Barley, E.; Cates, CJ. (2010). Welsh, Emma J. ed. "Caffeine for asthma". Cochrane Database of Systematic Reviews (1): CD001112. doi:10.1002/14651858.CD001112.pub2. PMID 20091514.
- Mathew OP (2011). "Apnea of prematurity: pathogenesis and management strategies". J Perinatol 31 (5): 302–10. doi:10.1038/jp.2010.126. PMID 21127467.
- Kugelman A, Durand M (2011). "A comprehensive approach to the prevention of bronchopulmonary dysplasia". Pediatr Pulmonol 46 (12): 1153–65. doi:10.1002/ppul.21508. PMID 21815280.
- Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W (2006). "Caffeine therapy for apnea of prematurity". N. Engl. J. Med. 354 (20): 2112–21. doi:10.1056/NEJMoa054065. PMID 16707748.
- Schmidt B (2005). "Methylxanthine therapy for apnea of prematurity: evaluation of treatment benefits and risks at age 5 years in the international Caffeine for Apnea of Prematurity (CAP) trial". Biol. Neonate 88 (3): 208–13. doi:10.1159/000087584. PMID 16210843.
- Funk GD (2009). "Losing sleep over the caffeination of prematurity". J. Physiol. (Lond.) 587 (Pt 22): 5299–300. doi:10.1113/jphysiol.2009.182303. PMID 19915211.
- Schmidt B, Roberts RS, Davis P, Doyle LW, Barrington KJ, Ohlsson A, Solimano A, Tin W (November 2007). "Long-term effects of caffeine therapy for apnea of prematurity". N. Engl. J. Med. 357 (19): 1893–902. doi:10.1056/NEJMoa073679. PMID 17989382.
- Schmidt B, Anderson PJ, Doyle LW, Dewey D, Grunau RE, Asztalos EV, Davis PG, Tin W, Moddemann D, Solimano A, Ohlsson A, Barrington KJ, Roberts RS (January 2012). "Survival without disability to age 5 years after neonatal caffeine therapy for apnea of prematurity". JAMA 307 (3): 275–82. doi:10.1001/jama.2011.2024. PMID 22253394.
- Maughan RJ, Griffin J (2003). "Caffeine ingestion and fluid balance: a review". J Hum Nutr Diet 16 (6): 411–20. doi:10.1046/j.1365-277X.2003.00477.x. PMID 19774754.
- Anahad O'connor (4 March 2008). "Really? The claim: caffeine causes dehydration". New York Times. http://www.nytimes.com/2008/03/04/health/nutrition/04real.html?_r=1. Retrieved 3 August 2009.
- Armstrong LE, Casa DJ, Maresh CM, Ganio MS (2007). "Caffeine, fluid-electrolyte balance, temperature regulation, and exercise-heat tolerance". Exerc Sport Sci Rev 35 (3): 135–40. doi:10.1097/jes.0b013e3180a02cc1. PMID 17620932.
- "Caffeine". MedlinePlus: U.S. National Library of Medicine. http://www.nlm.nih.gov/medlineplus/caffeine.html. Retrieved 27 October 2012.
- American Psychiatric Association. (1994). Diagnostic and Statistical Manual of Mental Disorders (4th ed.). American Psychiatric Association. ISBN 0-89042-062-9.
- Lara DR (2010). "Caffeine, mental health, and psychiatric disorders". J. Alzheimers Dis. 20 Suppl 1: S239–48. doi:10.3233/JAD-2010-1378. PMID 20164571.
- Santos C, Costa J, Santos J, Vaz-Carneiro A, Lunet N (2010). "Caffeine intake and dementia: systematic review and meta-analysis". J. Alzheimers Dis. 20 Suppl 1: S187–204. doi:10.3233/JAD-2010-091387. PMID 20182026.
- Marques S, Batalha VL, Lopes LV, Outeiro TF (2011). "Modulating Alzheimer's disease through caffeine: a putative link to epigenetics". J. Alzheimers Dis. 24 (2): 161–71. doi:10.3233/JAD-2011-110032. PMID 21427489.
- Arendash GW, Cao C (2010). "Caffeine and coffee as therapeutics against Alzheimer's disease". J. Alzheimers Dis. 20 Suppl 1: S117–26. doi:10.3233/JAD-2010-091249. PMID 20182037.
- Winston AP (2005). "Neuropsychiatric effects of caffeine". Advances in Psychiatric Treatment 11 (6): 432–439. doi:10.1192/apt.11.6.432.
- Hughes RN (June 1996). "Drugs Which Induce Anxiety: Caffeine". New Zealand Journal of Psychology 25 (1): 36–42. doi:10.1016/S0278-6915(02)00096-0. PMID 12204388. http://www.psychology.org.nz/cms_show_download.php?id=766.
- Vilarim MM, Rocha Araujo DM, Nardi AE (August 2011). "Caffeine challenge test and panic disorder: a systematic literature review". Expert Rev Neurother 11 (8): 1185–95. doi:10.1586/ern.11.83. PMID 21797659.
- Smith A (September 2002). "Effects of caffeine on human behavior". Food Chem. Toxicol. 40 (9): 1243–55. doi:10.1016/S0278-6915(02)00096-0. PMID 12204388.
- Nehlig A (2010). "Is caffeine a cognitive enhancer?". J. Alzheimers Dis. 20 Suppl 1: S85–94. doi:10.3233/JAD-2010-091315. PMID 20182035.
- Jarvis MJ (1993). "Does caffeine intake enhance absolute levels of cognitive performance?". Psychopharmacology (Berl.) 110 (1–2): 45–52. doi:10.1007/BF02246949. PMID 7870897. http://link.springer.com/article/10.1007%2FBF02246949?LI=true.
- Bruce MS, Lader M (February 1989). "Caffeine abstention in the management of anxiety disorders". Psychol Med 19 (1): 211–4. doi:10.1017/S003329170001117X. PMID 2727208.
- "Caffeine (Systemic)". MedlinePlus. 25 May 2000. Archived from the original on 23 February 2007. https://web.archive.org/web/20070223063601/http://www.nlm.nih.gov/medlineplus/druginfo/uspdi/202105.html. Retrieved 3 August 2009.
- "Caffeine overdose". MedlinePlus. 4 April 2006. http://www.nlm.nih.gov/medlineplus/ency/article/002579.htm. Retrieved 3 August 2009.
- Verkhratsky A (January 2005). "Physiology and pathophysiology of the calcium store in the endoplasmic reticulum of neurons". Physiol. Rev. 85 (1): 201–79. doi:10.1152/physrev.00004.2004. PMID 15618481.
- Holmgren P, Nordén-Pettersson L, Ahlner J (2004). "Caffeine fatalities – four case reports". Forensic Science International 139 (1): 71–3. doi:10.1016/j.forsciint.2003.09.019. PMID 14687776.
- Alstott RL, Miller AJ, Forney RB (1973). "Report of a human fatality due to caffeine". Journal of Forensic Science 18 (35).
- Peters JM (1967). "Factors Affecting Caffeine Toxicity: A Review of the Literature". The Journal of Clinical Pharmacology and the Journal of New Drugs 7 (7): 131–141. doi:10.1002/j.1552-4604.1967.tb00034.x. http://jcp.sagepub.com/content/7/3/131.extract.
- Rodopoulos N, Wisén O, Norman A (May 1995). "Caffeine metabolism in patients with chronic liver disease". Scand. J. Clin. Lab. Invest. 55 (3): 229–42. doi:10.3109/00365519509089618. PMID 7638557.
- Cheston P, Smith L (11 October 2013). "Man died after overdosing on caffeine mints". The Independent. http://www.independent.co.uk/news/uk/home-news/man-died-after-overdosing-on-caffeine-mints-8874964.html. Retrieved 13 October 2013.
- Prynne M (11 October 2013). "Warning over caffeine sweets after father dies from overdose". The Telegraph. http://www.telegraph.co.uk/health/healthnews/10371921/Warning-over-caffeine-sweets-after-father-dies-from-overdose.html. Retrieved 13 October 2013.
- Fricker M (12 October 2013). "John Jackson: Family of dad who died from caffeine overdose after eating MINTS want them removed from sale". Mirror. http://www.mirror.co.uk/news/uk-news/john-jackson-family-dad-who-2363193. Retrieved 13 October 2013.
- Kerrigan S, Lindsey T (2005). "Fatal caffeine overdose: two case reports". Forensic Sci. Int. 153 (1): 67–9. doi:10.1016/j.forsciint.2005.04.016. PMID 15935584.
- "Information about caffeine dependence". http://www.caffeinedependence.org/caffeine_dependence.html. Retrieved 25 May 2012.
- Juliano LM, Griffiths RR (2004). "A critical review of caffeine withdrawal: empirical validation of symptoms and signs, incidence, severity, and associated features". Psychopharmacology (Berl.) 176 (1): 1–29. doi:10.1007/s00213-004-2000-x. PMID 15448977. Archived from the original on 29 January 2012. http://webcitation.org/6533BsxXt.
- Silverman K, Evans SM, Strain EC, Griffiths RR (October 1992). "Withdrawal syndrome after the double-blind cessation of caffeine consumption". N. Engl. J. Med. 327 (16): 1109–14. doi:10.1056/NEJM199210153271601. PMID 1528206.
- Matt Peckham (31 May 2013). "Caffeine Withdrawal Is Now a Mental Disorder". Time. http://newsfeed.time.com/2013/05/31/caffeine-withdrawal-is-now-a-mental-disorder/#ixzz2VGUqUg1D.
- "Caffeine Content of Food and Drugs". Nutrition Action Health Newsletter. Center for Science in the Public Interest. 1996. Archived from the original on 14 June 2007. https://web.archive.org/web/20070614144016/http://www.cspinet.org/nah/caffeine/caffeine_content.htm. Retrieved 3 August 2009.
- "Caffeine Content of Beverages, Foods, & Medications". The Vaults of Erowid. 7 July 2006. http://www.erowid.org/chemicals/caffeine/caffeine_info1.shtml. Retrieved 3 August 2009.
- "Caffeine Content of Drinks". Caffeine Informer. http://www.caffeineinformer.com/the-caffeine-database. Retrieved 8 December 2013.
- Chin JM, Merves ML, Goldberger BA, Sampson-Cone A, Cone EJ (October 2008). "Caffeine content of brewed teas". J Anal Toxicol 32 (8): 702–4. doi:10.1093/jat/32.8.702. PMID 19007524.
- Richardson, Bruce (2009). "Too Easy to be True. De-bunking the At-Home Decaffeination Myth". Elmwood Inn. http://www.elmwoodinn.com/about/caffeine.html. Retrieved 12 January 2012.
- "Traditional Yerba Mate in Biodegradable Bag". Guayaki Yerba Mate. http://guayaki.com/product/41/Traditional-Yerba-Mate-%5B1-lb.%5D.html. Retrieved 17 July 2010.
- Geoffrey Burchfield (1997). "What's your poison: caffeine". Australian Broadcasting Corporation. http://www.abc.net.au/quantum/poison/caffeine/caffeine.htm. Retrieved 15 January 2014.
- Frischknecht PM, Ulmer-Dufek J, Baumann TW (1986). "Purine alkaloid formation in buds and developing leaflets of Coffea arabica: Expression of an optimal defence strategy?". Phytochemistry 25 (3): 613–6. doi:10.1016/0031-9422(86)88009-8.
- Nathanson JA (1984). "Caffeine and related methylxanthines: possible naturally occurring pesticides". Science 226 (4671): 184–7. doi:10.1126/science.6207592. PMID 6207592.
- Baumann TW (1984). "Metabolism and excretion of caffeine during germination of Coffea arabica L". Plant and Cell Physiology 25 (8): 1431–6. http://pcp.oxfordjournals.org/content/25/8/1431.abstract.
- Wright GA, Baker DD, Palmer MJ, Stabler D, Mustard JA, Power EF, Borland AM, Stevenson PC (March 2013). "Caffeine in floral nectar enhances a pollinator's memory of reward". Science 339 (6124): 1202–4. doi:10.1126/science.1228806. PMID 23471406.
- Matissek R (1997). "Evaluation of xanthine derivatives in chocolate: nutritional and chemical aspects". European Food Research and Technology 205 (3): 175–84. doi:10.1007/s002170050148. Template:INIST.
- "Does Yerba Maté Contain Caffeine or Mateine?". The Vaults of Erowid. 2003. http://www.erowid.org/plants/yerba_mate/yerba_mate_chemistry1.shtml. Retrieved 3 August 2009.
- "PubChem: mateina". National Library of Medicine. http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?db=pccompound&term=mateina. Retrieved 3 August 2009. . Generally translated as mateine in articles written in English
- Balentine D. A., Harbowy M. E. and Graham H. N. (1998). G Spiller. ed. Tea: the Plant and its Manufacture; Chemistry and Consumption of the Beverage. Template:Clarify
- "Caffeine". International Coffee Organization. http://www.ico.org/caffeine.asp. Retrieved 1 August 2009.
- "Coffee and Caffeine FAQ: Does dark roast coffee have less caffeine than light roast?". http://coffeefaq.com/site/node/15. Retrieved 2 August 2009.
- "All About Coffee: Caffeine Level". Jeremiah's Pick Coffee Co. Archived from the original on 18 March 2008. https://web.archive.org/web/20080318102343/http://www.jeremiahspick.com/caffeine-e-13.html. Retrieved 3 August 2009.
- Hicks MB, Hsieh Y-H P, Bell LN (1996). "Tea preparation and its influence on methylxanthine concentration". Food Research International 29 (3–4): 325–330. doi:10.1016/0963-9969(96)00038-5.
- Bempong DK, Houghton PJ, Steadman K (1993). "The xanthine content of guarana and its preparations". Int J Pharmacog 31 (3): 175–181. doi:10.3109/13880209309082937. ISSN 0925-1618.
- Smit HJ, Gaffan EA, Rogers PJ (November 2004). "Methylxanthines are the psycho-pharmacologically active constituents of chocolate". Psychopharmacology (Berl.) 176 (3–4): 412–9. doi:10.1007/s00213-004-1898-3. PMID 15549276.
- Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. p. 195. ISBN 978-0-415-92723-9. http://books.google.com/?id=YdpL2YCGLVYC&pg=PA195. Retrieved 15 January 2014.
- "LeBron James Shills for Sheets Caffeine Strips, a Bad Idea for Teens, Experts Say". ABC News. 10 June 2011. http://abcnews.go.com/Health/lebron-james-shills-sheets-caffeine-strips-bad-idea/story?id=13805037. Retrieved 25 May 2012.
- Nancy Shute (15 April 2007). "Over The Limit:Americans young and old crave high-octane fuel, and doctors are jittery". US News and World Reports. http://health.usnews.com/usnews/health/articles/070415/23caffeine_6.htm. [dead link]
- "F.D.A. Inquiry Leads Wrigley to Halt ‘Energy Gum’ Sales". New York Times. Associated Press. 8 May 2013. http://www.nytimes.com/2013/05/09/business/fda-inquiry-leads-wrigley-to-halt-energy-gum-sales.html. Retrieved 9 May 2013.
- http://www.washingtonpost.com/business/controversy-over-inhaled-caffeine-grows-as-as-sen-schumer-calls-for-fda-probe/2011/12/22/gIQAjQaVDP_story.html[dead link]
- "Caffeine biosynthesis". The Enzyme Database. Trinity College Dublin. http://www.enzyme-database.org/reaction/misc/caffeine.html. Retrieved 24 September 2011.
- Temple NJ, Wilson T (2003). Beverages in Nutrition and Health. Totowa, NJ: Humana Press. p. 172. ISBN 1-58829-173-1.
- Template:Cite patent
- Susan Budavari, ed (1996). The Merck Index (12th ed.). Whitehouse Station, NJ: Merck & Co., Inc.. p. 1674.
- This is the pKa for protonated caffeine, given as a range of values included in Harry G. Brittain, Richard J. Prankerd (2007). Profiles of Drug Substances, Excipients and Related Methodology, volume 33: Critical Compilation of pKa Values for Pharmaceutical Substances. Academic Press. p. 15. ISBN 0-12-260833-X. http://books.google.com/books?id=D3vBu5Tx4XwC&pg=PA15. Retrieved 15 January 2014.
- Klosterman L (2006). The Facts About Caffeine (Drugs). Benchmark Books (NY). p. 43. ISBN 0-7614-2242-0.
- Vallombroso T (2001). Organic Chemistry Pearls of Wisdom. Boston Medical Publishing Corp. p. 43. ISBN 1-58409-016-2.
- Keskineva N. "Chemistry of Caffeine" (PDF). Chemistry Department, East Stroudsburg University. http://quantum.esu.edu/~scady/Chem495/keskineva.pdf. Retrieved 2 January 2014.
- Ashihara H, Monteiro AM, Gillies FM, Crozier A (1996). "Biosynthesis of Caffeine in Leaves of Coffee". Plant Physiol. 111 (3): 747–753. doi:10.1104/pp.111.3.747. PMID 12226327.
- Simon Tilling. "Crystalline Caffeine". Bristol University. http://www.chm.bris.ac.uk/webprojects2001/tilling/synthesis.htm. Retrieved 3 August 2009.
- Zajac MA, Zakrzewski AG, Kowal MG, Narayan S (2003). "A Novel Method of Caffeine Synthesis from Uracil". Synthetic Communications 33 (19): 3291–3297. doi:10.1081/SCC-120023986. http://www.umich.edu/~chemh215/CHEM216/Honors%20Cup_old/HCProposal/caffeine.pdf.
- Jinka TR, Tøien Ø, Drew KL (2011). "Season primes the brain in an arctic hibernator to facilitate entrance into torpor mediated by adenosine A(1) receptors". J. Neurosci. 31 (30): 10752–8. doi:10.1523/JNEUROSCI.1240-11.2011. PMID 21795527.
- "World of Caffeine". World of Caffeine. 15 June 2013. http://worldofcaffeine.com/caffeine-and-neurotransmitters/. Retrieved 19 December 2013.
- Fisone G, Borgkvist A, Usiello A (2004). "Caffeine as a psychomotor stimulant: mechanism of action". Cell. Mol. Life Sci. 61 (7–8): 857–72. doi:10.1007/s00018-003-3269-3. PMID 15095008.
- Latini S, Pedata F (2001). "Adenosine in the central nervous system: release mechanisms and extracellular concentrations". J. Neurochem. 79 (3): 463–84. doi:10.1046/j.1471-4159.2001.00607.x. PMID 11701750.
- Basheer R, Strecker RE, Thakkar MM, McCarley RW (2004). "Adenosine and sleep-wake regulation". Prog. Neurobiol. 73 (6): 379–96. doi:10.1016/j.pneurobio.2004.06.004. PMID 15313333.
- Huang ZL, Qu WM, Eguchi N, Chen JF, Schwarzschild MA, Fredholm BB, Urade Y, Hayaishi O (July 2005). "Adenosine A2A, but not A1, receptors mediate the arousal effect of caffeine". Nat. Neurosci. 8 (7): 858–9. doi:10.1038/nn1491. PMID 15965471.
- Ribeiro JA, Sebastião AM (2010). "Caffeine and adenosine". J. Alzheimers Dis. 20 Suppl 1: S3–15. doi:10.3233/JAD-2010-1379. PMID 20164566.
- Essayan DM (November 2001). "Cyclic nucleotide phosphodiesterases". J. Allergy Clin. Immunol. 108 (5): 671–80. doi:10.1067/mai.2001.119555. PMID 11692087.
- Deree J, Martins JO, Melbostad H, Loomis WH, Coimbra R (June 2008). "Insights into the regulation of TNF-alpha production in human mononuclear cells: the effects of non-specific phosphodiesterase inhibition". Clinics (Sao Paulo) 63 (3): 321–8. doi:10.1590/S1807-59322008000300006. PMID 18568240.
- Marques LJ, Zheng L, Poulakis N, Guzman J, Costabel U (February 1999). "Pentoxifylline inhibits TNF-alpha production from human alveolar macrophages". Am. J. Respir. Crit. Care Med. 159 (2): 508–11. doi:10.1164/ajrccm.159.2.9804085. PMID 9927365. http://ajrccm.atsjournals.org/cgi/pmidlookup?view=long&pmid=9927365.
- Peters-Golden M, Canetti C, Mancuso P, Coffey MJ. (2005). "Leukotrienes: underappreciated mediators of innate immune responses". Journal of Immunology 174 (2): 589–94. PMID 15634873. http://www.jimmunol.org/cgi/content/full/174/2/589.
- Davis JK, Green JM (2009). "Caffeine and anaerobic performance: ergogenic value and mechanisms of action". Sports Med 39 (10): 813–32. doi:10.2165/11317770-000000000-00000. PMID 19757860.
- McArdle W (2010). Exercise Physiology (7th ed.). Baltimore, MD: Lippincott Williams and Wilkins. p. 559. ISBN 978-0-7817-9781-8.
- Dews PB (1984). Caffeine: Perspectives from Recent Research. Berlin: Springer-Valerag. ISBN 978-0-387-13532-8.
- Liguori A, Hughes JR, Grass JA (1997). "Absorption and subjective effects of caffeine from coffee, cola and capsules". Pharmacol. Biochem. Behav. 58 (3): 721–6. doi:10.1016/S0091-3057(97)00003-8. PMID 9329065.
- "Koffazon". Swedish Drug Catalog. 10 February 2010. http://www.fass.se/LIF/produktfakta/artikel_produkt.jsp?NplID=20030808000012&DocTypeID=6#pharmacokinetic.
- Newton R, Broughton LJ, Lind MJ, Morrison PJ, Rogers HJ, Bradbrook ID (1981). "Plasma and salivary pharmacokinetics of caffeine in man". Eur. J. Clin. Pharmacol. 21 (1): 45–52. doi:10.1007/BF00609587. PMID 7333346.
- Graham JR (1954). "Rectal use of ergotamine tartrate and caffeine alkaloid for the relief of migraine". N. Engl. J. Med. 250 (22): 936–8. doi:10.1056/NEJM195406032502203. PMID 13165929.
- Brødbaek HB, Damkier P (2007). "The treatment of hyperemesis gravidarum with chlorobutanol-caffeine rectal suppositories in Denmark: practice and evidence" (in Danish). Ugeskr. Laeg. 169 (22): 2122–3. PMID 17553397.
- "Drug Interaction: Caffeine Oral and Fluvoxamine Oral". Medscape Multi-Drug Interaction Checker. http://www.medscape.com/druginfo/druginteractions?drug_408=Caffeine%20Oral&drug_1049=Fluvoxamine%20Oral.
- Hammami, M. M., Al-Gaai, E. A., Alvi, S., & Hammami, M. B. (2010). "Interaction between drug and placebo effects: A cross-over balanced placebo design trial". Trials 11 (110): 1–10. doi:10.1186/1745-6215-11-110. PMID 21092089.
- "Caffeine". The Pharmacogenetics and Pharmacogenomics Knowledge Base. http://www.pharmgkb.org/do/serve?objId=PA448710&objCls=Drug&tabType=Properties#biotransformation. Retrieved 25 October 2010.
- Verbeeck RK (2008). "Pharmacokinetics and dosage adjustment in patients with hepatic dysfunction". Eur. J. Clin. Pharmacol. 64 (12): 1147–61. doi:10.1007/s00228-008-0553-z. PMID 18762933.
- Janknegt R (1990). "Drug interactions with quinolones". J. Antimicrob. Chemother. 26 Suppl D: 7–29. doi:10.1093/jac/26.suppl_D.7. PMID 2286594.
- Cornelis MC, Monda KL, Yu K, Paynter N, Azzato EM, Bennett SN, Berndt SI, Boerwinkle E, Chanock S, Chatterjee N, Couper D, Curhan G, Heiss G, Hu FB, Hunter DJ, Jacobs K, Jensen MK, Kraft P, Landi MT, Nettleton JA, Purdue MP, Rajaraman P, Rimm EB, Rose LM, Rothman N, Silverman D, Stolzenberg-Solomon R, Subar A, Yeager M, Chasman DI, van Dam RM, Caporaso NE (April 2011). Gibson, Greg. ed. "Genome-wide meta-analysis identifies regions on 7p21 (AHR) and 15q24 (CYP1A2) as determinants of habitual caffeine consumption". PLoS Genet. 7 (4): e1002033. doi:10.1371/journal.pgen.1002033. PMID 21490707.
- Baselt R (2011). Disposition of Toxic Drugs and Chemicals in Man (9th ed.). Seal Beach, CA: Biomedical Publications. pp. 236–9. ISBN 0-931890-08-X.
- Senese F (20 September 2005). "How is coffee decaffeinated?". General Chemistry Online. http://antoine.frostburg.edu/chem/senese/101/consumer/faq/decaffeinating-coffee.shtml. Retrieved 3 August 2009.
- McCusker RR, Fuehrlein B, Goldberger BA, Gold MS, Cone EJ (October 2006). "Caffeine content of decaffeinated coffee". J Anal Toxicol 30 (8): 611–3. doi:10.1093/jat/30.8.611. PMID 17132260. Lay summary – University of Florida News.
- John C. Evans (1992). Tea in China: The History of China's National Drink. Greenwood Press. p. 2. ISBN 0-313-28049-5.
- Yu L (1995). The Classic of Tea: Origins & Rituals. Ecco Pr. ISBN 0-88001-416-4. Template:Page needed
- Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. pp. 3–4. ISBN 978-0-415-92723-9.
- Meyers, Hannah (7 March 2005). ""Suave Molecules of Mocha" – Coffee, Chemistry, and Civilization". New Partisan. Archived from the original on 9 March 2005. https://web.archive.org/web/20050309110855/http://www.newpartisan.com/home/suave-molecules-of-mocha-coffee-chemistry-and-civilization.html. Retrieved 3 February 2007.
- Benjamin LT, Rogers AM, Rosenbaum A (1991). "Coca-Cola, caffeine, and mental deficiency: Harry Hollingworth and the Chattanooga trial of 1911". J Hist Behav Sci 27 (1): 42–55. doi:10.1002/1520-6696(199101)27:1<42::AID-JHBS2300270105>3.0.CO;2-1. PMID 2010614.
- "The Rise and Fall of Cocaine Cola". http://www.lewrockwell.com/jarvis/jarvis17.html. Retrieved 25 May 2012. [unreliable source?]
- Fairbanks, Charles H. (2004). "The function of black drink among the Creeks". in Hudson, Charles M.. Black Drink. University of Georgia Press. p. 123. ISBN 978-0-8203-2696-2.
- Crown PL, Emerson TE, Gu J, Hurst WJ, Pauketat TR, Ward T (August 2012). "Ritual Black Drink consumption at Cahokia". Proc. Natl. Acad. Sci. U.S.A. 109 (35): 13944–13949. doi:10.1073/pnas.1208404109. PMID 22869743. PMC 3435207. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3435207/.
- Runge, Friedlieb Ferdinand (1820). Neueste phytochemische Entdeckungen zur Begründung einer wissenschaftlichen Phytochemie [Latest phytochemical discoveries for the founding of a scientific phytochemistry]. Berlin: G. Reimer. pp. 144–159. http://books.google.com/books?id=KLg5AAAAcAAJ&pg=P146. Retrieved 8 January 2014.
- In 1819, Runge was invited to show Goethe how belladonna caused dilation of the pupil, which Runge did, using a cat as an experimental subject. Goethe was so impressed with the demonstration that: "Nachdem Goethe mir seine größte Zufriedenheit sowol über die Erzählung des durch scheinbaren schwarzen Staar Geretteten, wie auch über das andere ausgesprochen, übergab er mir noch eine Schachtel mit Kaffeebohnen, die ein Grieche ihm als etwas Vorzügliches gesandt. "Auch diese können Sie zu Ihren Untersuchungen brauchen," sagte Goethe. Er hatte recht; denn bald darauf entdeckte ich darin das, wegen seines großen Stickstoffgehaltes so berühmt gewordene Coffein." (After Goethe had expressed to me his greatest satisfaction regarding the account of the man [whom I'd] rescued [from serving in Napoleon's army] by apparent "black star" [i.e., amaurosis, blindness] as well as the other, he handed me a carton of coffee beans, which a Greek had sent him as a delicacy. "You can also use these in your investigations," said Goethe. He was right; for soon thereafter I discovered therein caffeine, which became so famous on account of its high nitrogen content.)
This account appeared in Runge's book Hauswirtschaftlichen Briefen (Domestic Letters [i.e., personal correspondence]) of 1866. It was reprinted in: Johann Wolfgang von Goethe with F.W. von Biedermann, ed., Goethes Gespräche, vol. 10: Nachträge, 1755–1832 (Leipzig, (Germany): F.W. v. Biedermann, 1896), pages 89–96; see especially page 95.
- Bennett Alan Weinberg, Bonnie K. Bealer (2001). The World of Caffeine: The Science and Culture of the World's Most Popular Drug. Routledge. ISBN 978-0-415-92723-9. Template:Page needed
- Berzelius, Jöns Jakob (1825). "[Annual report on the progress of the physical sciences by Jacob Berzelius]" (in German). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius. 4. p. 180. http://books.google.com/books?id=XJI8AAAAIAAJ&pg=RA1-PA180. From page 180: "Caféin ist eine Materie im Kaffee, die zu gleicher Zeit, 1821, von Robiquet und Pelletier und Caventou entdekt wurde, von denen aber keine etwas darüber im Drucke bekannt machte." (Caffeine is a material in coffee, which was discovered at the same time, 1821, by Robiquet and [by] Pelletier and Caventou, by whom however nothing was made known about it in the press.)
- Berzelius JJ (1828) (in German). Jahres-Bericht über die Fortschritte der physischen Wissenschaften von Jacob Berzelius [Annual Report on the Progress of the Physical Sciences by Jacob Berzelius]. 7. p. 270. http://books.google.com/books?id=iGs1AAAAcAAJ&pg=P270. From page 270: "Es darf indessen hierbei nicht unerwähnt bleiben, dass Runge (in seinen phytochemischen Entdeckungen 1820, p. 146-7.) dieselbe Methode angegeben, und das Caffein unter dem Namen Caffeebase ein Jahr eher beschrieben hat, als Robiquet, dem die Entdeckung dieser Substanz gewöhnlich zugeschrieben wird, in einer Zusammenkunft der Societé de Pharmacie in Paris die erste mündliche Mittheilung darüber gab." (However, at this point, it should not remain unmentioned that Runge (in his Phytochemical Discoveries, 1820, pages 146–147) specified the same method and described caffeine under the name Caffeebase a year earlier than Robiquet, to whom the discovery of this substance is usually attributed, having made the first oral announcement about it at a meeting of the Pharmacy Society in Paris.)
- Pelletier, Pierre Joseph (1822). "Cafeine" (in French). Dictionnaire de Médecine. 4. Paris: Béchet Jeune. pp. 35–36. http://books.google.com/books?id=rFw_AAAAcAAJ&pg=PA35. Retrieved 3 March 2011.
- Robiquet, Pierre Jean (1823). "Cafe" (in French). Dictionnaire Technologique, ou Nouveau Dictionnaire Universel des Arts et Métiers. 4. Paris: Thomine et Fortic. pp. 50–61. http://cnum.cnam.fr/CGI/gpage.cgi?p1=50. Retrieved 3 March 2011.
- Dumas and Pelletier (1823). "Recherches sur la composition élémentaire et sur quelques propriétés caractéristiques des bases salifiables organiques [Studies into the elemental composition and some characteristic properties of organic bases]" (in French). Annales de Chimie et de Physique 24: 163–191. http://books.google.com/books?id=-BIAAAAAMAAJ&pg=PA182.
- Oudry M (1827). "Note sur la Théine" (in French). Nouvelle bibliothèque médicale 1: 477–479. http://books.google.com/books?id=cGpEAAAAcAAJ&pg=PA477.
- Mulder, G. J. (1838). "Ueber Theïn und Caffeïn [Concerning theine and caffeine]". Journal für Praktische Chemie 15: 280–284. doi:10.1002/prac.18380150124. http://books.google.com/books?id=HQHzAAAAMAAJ&pg=PA280.
- Jobst, Carl (1838). "Thein identisch mit Caffein [Theine is identical to caffeine)]". Liebig's Annalen der Chemie und Pharmacie 25: 63–66. doi:10.1002/jlac.18380250106. http://books.google.com/books?id=teJSAAAAcAAJ&pg=PA63.
- Fischer began his studies of caffeine in 1881; however, understanding of the molecule's structure long eluded him. In 1895 he synthesized caffeine, but only in 1897 did he finally fully determine its molecular structure.
- Fischer E (1881). "Ueber das Caffeïn [On caffeine]" (in German). Berichte der Deutschen chemischen Gesellschaft zu Berlin 14: 637–644. doi:10.1002/cber.188101401142. http://gallica.bnf.fr/ark:/12148/bpt6k90692z/f640.image.langEN.
- Fischer E (1881). "Ueber das Caffeïn. Zweite Mitteilung [On caffeine. Second communication.]" (in German). Berichte der Deutschen chemischen Gesellschaft zu Berlin 14 (2): 1905–1915. doi:10.1002/cber.18810140283. http://gallica.bnf.fr/ark:/12148/bpt6k906939/f316.image.langEN.
- Fischer E (1882). "Ueber das Caffeïn. Dritte Mitteilung [On caffeine. Third communication.]" (in German). Berichte der Deutschen chemischen Gesellschaft zu Berlin 15: 29–33. doi:10.1002/cber.18820150108. http://gallica.bnf.fr/ark:/12148/bpt6k90694n/f32.image.langEN.
- Fischer E, Ach L (1895). "Synthese des Caffeïns [On caffeine. Third communication.]" (in German). Berichte der Deutschen chemischen Gesellschaft zu Berlin 28 (3): 3135–3143. doi:10.1002/cber.189502803156. http://gallica.bnf.fr/ark:/12148/bpt6k907400/f806.image.langEN.
- Fischer E (1897). "Ueber die Constitution des Caffeïns, Xanthins, Hypoxanthins und verwandter Basen [On the constitution of caffeine, xanthin, hypoxanthin, and related bases.]" (in German). Berichte der Deutschen chemischen Gesellschaft zu Berlin 30: 549–559. doi:10.1002/cber.189703001110. http://gallica.bnf.fr/ark:/12148/bpt6k907462/f553.image.langEN.
- Hj. Théel (1902). "Nobel Prize Presentation Speech". http://nobelprize.org/nobel_prizes/chemistry/laureates/1902/press.html. Retrieved 3 August 2009.
- "Code of Federal Regulations Title 21". Code of Federal Regulations Title 21. 30 July 2013. http://www.accessdata.fda.gov/scripts/cdrh/cfdocs/cfCFR/CFRSearch.cfm?fr=182.1180&SearchTerm=caffeine.
- Brown, Daniel W (2004). A new introduction to Islam. Chichester, West Sussex: Wiley-Blackwell. pp. 149–51. ISBN 1-4051-5807-7.
- Ágoston, Gábor; Masters, Bruce (2009). Encyclopedia of the Ottoman Empire. p. 138. ISBN 978-1-4381-1025-7. http://books.google.com/?id=QjzYdCxumFcC&pg=PA138.
- Hopkins, Kate (24 March 2006). "Food Stories: The Sultan's Coffee Prohibition". Accidental Hedonist. http://accidentalhedonist.com/food-stories-the-sultans-coffee-prohibition/. Retrieved 3 January 2010.
- "By the King. A PROCLAMATION FOR THE Suppression of Coffee-Houses". http://www.uni-giessen.de/gloning/tx/suppress.htm. Retrieved 18 March 2012.
- Pendergrast 2001, p. 13
- Pendergrast 2001, p. 11
- Bersten 1999, p. 53
- Doctrine and Covenants Student Manual: Religion 324 and 325. Salt Lake City: LDS Church. 2001. p. 209. http://www.ldsces.org/inst_manuals/dc-in/dc-in-081.htm. Retrieved 15 January 2014.
- Juan Eduardo Campo (1 January 2009). Encyclopedia of Islam. Infobase Publishing. p. 154. ISBN 978-1-4381-2696-8. http://books.google.com/books?id=OZbyz_Hr-eIC&pg=PA154. Retrieved 1 November 2012.
- Daniel W. Brown (24 August 2011). A New Introduction to Islam. John Wiley & Sons. p. 149. ISBN 978-1-4443-5772-1.
- "Caffeine Poisoning in Dogs". AllPetsCo Pets Information. Pet Information. http://www.allpetsco.com/caffeine-poisoning-in-dogs/. Retrieved 29 February 2012.
- Paul, Dr. Lisa. "Why Caffeine is Toxic to Birds". HotSpot for Birds. Advin Systems. http://www.multiscope.com/hotspot/caffeine.htm. Retrieved 29 February 2012.
- Arnaud MJ (2011). "Pharmacokinetics and metabolism of natural methylxanthines in animal and man". Handb Exp Pharmacol. Handbook of Experimental Pharmacology (200): 33–91. doi:10.1007/978-3-642-13443-2_3. ISBN 978-3-642-13442-5. PMID 20859793.
- Noever R, Cronise J, Relwani RA (29 April 1995). "Using spider-web patterns to determine toxicity". NASA Tech Briefs (New Scientist magazine) 19 (4): 82. http://www.newscientist.com/article/mg14619750.500-spiders-on-speed-get-weaving.html.
- "Newly Discovered Bacteria Lives on Caffeine". Blogs.scientificamerican.com. 24 May 2011. http://blogs.scientificamerican.com/observations/2011/05/24/newly-discovered-bacteria-lives-on-caffeine. Retrieved 19 December 2013.
- Bersten, Ian (1999). Coffee, Sex & Health: A history of anti-coffee crusaders and sexual hysteria. Sydney: Helian Books. ISBN 0-9577581-0-3.
- Pendergrast, Mark (2001) . Uncommon Grounds: The History of Coffee and How It Transformed Our World. London: Texere. ISBN 1-58799-088-1.
- GMD MS Spectrum
- The Consumers Union Report on Licit and Illicit Drugs, Caffeine-Part 1 Part 2
- Caffeine: ChemSub Online
- Caffeine at The Periodic Table of Videos (University of Nottingham)
- Caffeine International Chemical Safety Cards
- Mayo Clinic staff (3 October 2009). "Caffeine content for coffee, tea, soda and more". Mayo Clinic. http://www.mayoclinic.com/health/caffeine/AN01211. Retrieved 8 November 2010.